The skin is the largest organ in the body with remarkable physiological and social functions. The epidermal portion of the skin is responsible for waterproofing the body and acting as a mechanical barrier; thus, it is associated with vital functions. Upon injury, the immediate response of the epidermis and its stem cells aims at the reestablishment of local homeostasis; however extensive injuries, often observed in burn patients, may overwhelm the capacity to heal. If the epidermis-driven homeostasis is not restored, the organism undergoes dehydration and increased chances for infection and death. New therapeutic strategies aiming at accelerated epithelial migration and accumulation of epithelial stem cells are in great need to improve the health of burn patients and the achievement of better clinical outcomes. Our research bridges new findings in the field of stem cell biology with recent understanding of the role of the phosphatidylinositide 3-kinases (PI3K) molecular mechanisms in response to epithelial injury. PTEN was initially identified as a negative regulator of the PI3K signaling, the main regulator of cell growth, metabolism, and survival. By targeted disrupting the PTEN gene from the epithelial layer of the skin containing stem cells, we observed a brisk activation of cellular proliferation associated with increased migration. Moreover, we found that disruption of PTEN from the epidermis also results in the accumulation of epithelial stem cells indicating a critical role of the PI3K signaling pathway in the maintenance of epithelial homeostasis and response to external injuries. Here, we propose a novel therapeutic strategy to treat wounds by increasing the population of skin stem cells at the donor site before the isolation and graft in the injured recipient site. Furthermore, we will determine the therapeutic effectiveness of pharmacological action on the PI3K signaling during the re-epithelization and scarring after burn. Human- relevant preclinical animal models will be used to test our hypothesis on the efficacy of the PI3K in the treatment of burn. This application is significant; once that will explore novel druggable pathways capable of accelerating epithelial migration and wound closure, induce accumulation of epidermal stem cells, and reduce the development of wound scar.